Spontaneous cervical artery dissections and implications for homocysteine☆

Introduction 

Over the past 5 to 10 years, the issue of cerebrovascular accidents (CVAs) and spinal manipulation has become a debate of ever-increasing intensity. A copious number of studies have investigated spinal manipulation as a putatative causative factor of CVAs1, 2, 3, 4, 5; however, a common theme among these is the failure to consider that the majority of vertebrobasilar accidents (VBAs) may be spontaneous, cumulative, or caused by factors other than spinal manipulation. The problem is not served by the sometimes hysterical reactions apparent in the media over the past 2 years in reaction to the flawed investigations.6, 7, 8, 9, 10, 11 In light of these recent reports, the entire phenomenon of spontaneous cervical artery dissections should be revisited to put this matter into a better perspective.

Dissection mechanism 

The mechanism of CVAs involves the vertebral and carotid arteries of the upper cervical spine. Following cervical manipulations in particular, the most common site of injury to the vertebral arterial system appears to be in the vicinity of the atlanto-occipital joint, where the vertical artery bends into a horizontal configuration, as shown in Figure 1. By a large majority, most postmanipulative strokes and stroke-like symptoms occur in the segment of the vertebral artery bounded by the transverse foramen of the C2 vertebra and the foramen magnum.12 Interestingly, it is precisely in the C1-2 region in which rotational maneuvers have been suggested to produce a slight elevation in the incident rate of CVAs.13 Trauma to the arterial wall occurs, producing either vasospasm or damage to the arterial wall itself, and subsequently leads to brain ischemia.

Fig 1. The vertebral artery between the atlas and axis vertebrae. Used with permission from Louis Sportelli, DC.

As described by Terrett,14 arterial traumatic mechanisms may be classified by 1 of 6 categories: (1) subintimal hematoma, (2) intimal tear, (3) intimal tear with embolic formation, (4) vessel wall dissection with subintimal hematoma (dissecting aneurysm), (5) vessel wall dissection with pseudoaneurysm formation, and (6) perivascular bleeding (false saccular aneurysm). Although one might suspect altered vertebral artery hemodynamics and reduced basilar perfusion to be consequences of diagnostic testing and/or spinal manipulation, it is primarily the vertebral arterial dissections (VADs) which have been implicated in the majority of stroke or stroke-like incidents12 to be directly attributable to spinal manipulation. VADs, therefore, will form the basis of the ensuing discussion.

Spontaneous VAD rates 

As shown in Table 1, the annual incidence of spontaneous VADs in hospital settings has been estimated to occur at the rate of 1 to 1.5 per 100,000 patients.15 The corresponding VAD incidence rate in community settings has been reported to be twice as high.16, 17 Using an estimated value of 10 from the literature to represent an average number of manipulations per patient per episode,23 it becomes apparent that the proposed exposure rate for CVAs attributed to spinal manipulation is equivalent to the spontaneous rates for cervical arterial dissections as reported.15, 16, 17 If the threat of stroke or stroke-like symptoms is to be properly assessed, therefore, at least half our attention needs to be directed toward the spontaneous events instead of primarily or solely on spinal manipulation.

Table 1. %Rates of stroke compared with incidence of arterial dissections

	Attributed cause	Rate (per million)
	Spontaneous, hospital-based15	10-15
	Spontaneous, community-based16, 17	25-30
	Cervical manipulation18	25
	Cervical manipulation19	10-20∗
	Cervical manipulation20	0
	Cervical manipulation21	6.4∗
	Cervical manipulation22	1.7∗

∗ Corrected to represent the average incidence per patient assuming the average number of manipulations per patient to equal 10, as reported in the literature.23

Genetic factors and elevated homocysteine 

A consortium of investigators from northern Italy have recently demonstrated that a genetic defect in humans (C677T MTHFR, a thermolabile variant of the enzyme tetrahydrofolate reductase with half the normal activity) is associated with elevated levels of the amino acid homocysteine.24 According to Figure 2, A and B, this is shown (1) by the failure of the reductase enzyme to generate sufficient quantities of N5-methyltetrahydrofolate (Fig 2, A), resulting in (2) the inability to convert sufficient quantities of homocysteine to methionine (Fig 2, B). This is due to the fact that there are inadequate amounts of the methyl donor cofactor N5-methyltetrahydrofolate to catalyze the reaction, with the result that the precursor to methionine (homocysteine) accumulates intracellularly.25

Fig 2. A, Role of N5, N10-methylenetetrahydrofolate reductase (MTHFR). B, Presumed relationship of MTHFR to homocysteine. Reproduced with permission.25

In comparing 3 groups of about 30 patients each, Pezzini et al24 indicated that spontaneous cervical artery dissections (sCADs) are represented in the pool of patients whose homocysteine levels exceed 12 μmol/L—more than 3 times as much as asymptomatic patients and more than twice as much as patients who have undergone ischemic strokes without arterial dissection. Direct correlations of elevated plasma homocysteine levels with the occurrence of sCAD were also demonstrated,24 a finding that is echoed elsewhere by the findings that (1) cervical artery dissection (CAD) patients had average homocysteine levels of 17.9 μmol/L, while asymptomatic patients reported 6.0 μmol/L26; and (2) homocysteine levels exceeding 10.2 μmol/L are associated with a doubling of vascular risk.27

What is the clinical significance of elevated homocysteine levels? For years, homocysteine has been implicated as a key component of atherosclerosis and cardiovascular diseases,27, 28, 29, 30, 31, 32, 33, 34, 35 but Pezzini et al24 and other investigations suggest a more direct role. A significant number of clues all point toward the disruption of the structure of collagen and elastin in the arterial wall:

All of these observations would be enhanced by elevated levels of homocysteine and suggest that the resulting potential defects of the extracellular matrix of the vessel wall may play a role in the pathogenesis of arterial dissection.

The Pezzini et al24 observations concerning a defective tetrahydrofolate reductase may extend to a second mechanism by which collagen structure is disrupted. As shown in Figure 2, A, the aberrant enzyme leads to an accumulation of the precursor N5,N10-methylenetetrahydrofolate. It is conceivable from the biochemical pathway shown in Figure 3 that this entity may then favor the catabolic conversion of glycine into serine.25 By coincidence, glycine, as the smallest existing amino acid, turns out to be an essential component in the repeating tripeptide sequence which constitutes collagen. As shown by Figure 4, virtually all the hairpin turns in the core of the helical structure of collagen are glycine residues25; any lack or substitution thereof would be expected to impart significant kinks and other aberrations to the collagen structure, rendering it more susceptible to spontaneous degradation.

Fig 3. Catabolic pathways for glycine and other amino acids. Reproduced with permission.25

Fig 4. Structure of collagen. a, Repeating tripeptide sequence Glycine-X-Proline or Glycine-X-Hydroxyproline adopts a left-handed helical structure with 3 residues/turn [Hyp used here]. b, Space-filling model of collagen helix shown in (a). c, Three of these helices wrap around one another with a right-handed twist. d, Three-standed collagen superhelix shown from one end, with glycine residues shown in black. Glycine, because of its small size, is required at the right junction where the 3 chains come into contact. Reproduced with permission.25

Other links between elevated homocysteine and CAD 

Links between increased plasma levels of homocysteine and vascular disease were proposed as early as in 1969.28 After a continuous 3-month infusion of homocysteine in baboons, vascular injury and thrombosis could be induced with patchy endothelial desquamation, observed on up to 10% of the aortic surface.33 In subjects with hyperhomocysteinemia, an impaired reaction of endothelium-dependent and flow-mediated dilation could be observed.34 Finally, in cell culture experiments, the addition of homocysteine into the cell medium induced the detachment of cells from the endothelial cell monolayer.40 The common denominator pertaining to risks associated with spinal manipulation is arterial wall fragility, rather than stenosis and the other cardiovascular risks which have been associated with elevated homocysteine.28, 29, 30, 31, 32

Practical implications of homocysteine determinations 

Until recently, the gold standard methodology for determining plasma homocysteine has been high pressure liquid chromatography, gas chromatography, and mass spectrometry.41, 42, 43 Fortunately, this cumbersome technology has recently been correlated with a much simpler enzyme conversion immunoassay (EIA).44 An even faster assay method by means of an automated analyzer is also available, requiring only microliter amounts of reagent and sample.45 This essentially means that homocysteine levels can be determined in any number of clinical reference laboratories already established to measure blood analytes.

To date, the assessment options for vertebrobasilar artery risk each have significant drawbacks (Table 2) and as a whole have been unable to identify any particular factor that is useful for screening.45, 46 Provocation tests, in particular, are problematic in that in several aspects they replicate the risks associated with cervical manipulation by requiring the placement of the head and neck in extreme extension and rotation.20, 48 False-negative findings compared with angiograms have been reported49; reliability and validity have not been reliably tested46; and the suggestion has been made that these tests be demphasized.50 In the midst of this disorder, determining homocysteine levels as a predictor of arterial fragility seems to be a plausible, rapid, and inexpensive procedure that is no more invasive than a routine blood glucose determination.

Table 2. %Current vertebrobasilar artery risk assessment options47

	Option	Value	Limitation
	Provocative testing	May provide some medicolegal protection.	Little or no actual clinical value; false-negative testing documented; false sense of security.
	Doppler ultrasound	Images vertebral arterial flow; may document dissection in evolution.	Manual compression and provocation testing does not appear to obstruct flow in symptomatic individuals or control subjects; normal in unoccluded arteries.
	CT, MRI scan	Images brain structure; of value in documenting completed infarct.	Does not image vertebral arteries very well.
	MRA	Visualizes vertebral arteries; localizes the dissection and occlusion.	High cost; limited availability; never investigated as a screening tool.
	Arteriography	Gold standard for visualizing vertebral arteries; can document congenital abnormalities.	Invasive test with known complication rate; expensive; not demonstrated to show patients at risk.

CT, computed tomography; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography.

Spontaneous rather than traumatic events precipitate CADs 

It would appear that arterial dissections due to trauma directly associated with spinal manipulation are unlikely, as experiments with arterial models at the University of Calgary have shown that peak elongations of the vertebral artery during neck manipulations are at most 11% of the elongations that would be seen at the arterial failure limits; in fact, these elongations are consistently lower than those seen during routine diagnostic tests.51

All of the preceding arguments have attempted to point out that the occurrence of arterial dissections is more subtle than that suggested by frank trauma. An appreciable body of literature exists to demonstrate that a wide variety of common lifestyle activities have been associated with cerebral ischemia (Table 3) 52 or even CVAs (Table 4) 53 but are decidedly nonmanipulative. By way of illustration, one very recent investigation has described beauty parlor stroke syndrome and salon sink radiculopathy, confirmed by both symptoms and blood flow velocities in the bilateral vertebral and carotid arteries as measured by a diagnostic ultrasound instrument.54

Table 3. %Selected activities suspected of disrupting cerebral circulation52

	Angiography
	Bleeding nose
	Axial traction
	Calisthenics
	Cervical extension for radiographs or CTS
	Cervical rotation while backing up a car
	Coughing
	Dental procedure
	Football
	Gymnastics
	Hanging out washing
	Overhead work
	Roller coaster
	Telephone call
	Traction and short wave diathermy
	Trampoline
	Watching aircraft
	Yawning

Table 4. %Nonmanipulative maneuvers associated with CVAs53

	Childbirth
	By surgeon or anethetist during surgery
	Calisthenics
	Yoga
	Overhead work
	Neck extension during radiography
	Neck extension for a bleeding nose
	Turning the head while driving a vehicle
	Archery
	Wrestling
	Emergency resuscitation
	Star gazing
	Sleeping position
	Swimming
	Rap dancing
	Fitness exercise
	Beauty parlor stroke
	Tai Chi

Thus, it would appear that the tearing of the arterial wall in a dissection is both cumulative and spontaenous: cumulative in that repeated, low-grade insults to the artery would most likely be required to yield a dissection; and spontaneous in that these more minor impositions appear to be by dint of any number of self-imposed maneuvers as well as any by a practitioner, making it extremely difficult if not impossible to distinguish between them. Finally, spontaneous dissections appear to correlate with the fragility of the arterial wall, which may be attributable to inborn errors of metabolism that might be detectable by means of a homocysteine assay.

Relative risks in perspective 

As shown above in Table 1, the bulk of the scientific literature establishes the presumed risk of cerebrovascular accidents (including stroke) associated with spinal manipulation at anywhere from 1 per 400,000 to 1 per 5.85 million cervical manipulations, the latter figure representing the most rigorously derived frequency to date.18, 19, 20, 21, 22 On the other hand, the risk of deaths from the use of medicines such as nonsteroidal anti-inflammatory agents (NSAIDs) or from surgery to treat many of the same conditions as those managed by chiropractors is 400 to 700 times greater; yet, warnings pertaining to the use of these particular options are often ignored in both common medical treatment and the media.55, 56

Death rates due to medication side effects have been estimated by the Institute of Medicine to range from 230,000 to 280,000 per year.57 Those caused by commonly used NSAIDs (such as ibuprofen) have been reported to approach an annual rate of 16,000, dwarfing any estimates of chiropractic fatalities by several orders of magnitude.58

How unsubstantiated or misinterpreted risk estimates regarding CVAs attributed to manipulation find their way into the public forum remains a matter of great concern. A troubling series of citations, which create the misleading impression of having data to support them, needs to be discussed in this regard. Such a problem surfaced in the public domain with the publication of an article on aterial trauma by the respected scientific writer Jane Brody for the New York Times. In April 2001, Brody stated that chiropractic spinal manipulation is “estimated to cause stroke in as many as 1 in 20,000 patients.”6 Her documentation for this statement was a paper by Wouter Schievink who, in the New England Journal of Medicine, indicated: “As many as 1 in 20,000 spinal manipulations causes a stroke.”59 As in Jane Brody's article, there were no data in Schievink's paper to support such a statement. Instead, the author quoted yet another study published by Andrew Vickers 2 years earlier in the British Medical Journal. Unfortunately, Vickers likewise failed to provide any data to support this contention but rather provided only the declaration: “Adverse events range from 1 in 20,000 patients undergoing cervical manipulation to 1 million procedures.”60 Through this entire trail of some of the most trusted medical journals, therefore, there is nothing more than the authors' opinions to support this rather drastic contention regarding stroke estimates attributable to spinal manipulation. Worse, the lowest frequency stated by the original author has been completely suppressed in citations in the subsequent scientific and popular literature. Only the suggested figure, which is 50-fold greater than the lower boundary, ever appears to have been carried forward and mentioned.

Dietary folate consumption: a possible solution 

As suggested by the biochemical pathways in Figure 2, B, it is conceivable that ensuring adequate levels of folate by dietary intake could depress elevated levels of homocysteine and alleviate the risk of stroke. Indeed, previous studies have shown there to be an inverse relationship between folate and homocysteine concentrations in the blood.29, 61, 62 Advancing this suggestion a step further is the dramatic finding from a follow-up study of the National Health and Nutrition Examination Survey (NHANES I) that in a population of 9764 noninstitutionalized US men and women aged 25 to 75 years, dietary intake of folate from food sources is independently and inversely related to the risk of stroke and cardiovascular disease. The relative risk for incident stroke and incident CVD events was 0.79 and 0.86 for patients with the highest daily folate intake (median value 405 μg/d) as compared with the lowest (median value 99 μg/d). In this particular investigation, folic acid supplements were not measured or taken into account in the analysis.63 With the national average of folate intake at 224 μg/d,64 food fortifications with an additional 95 μg/d in the diet of middle-aged and older adults have been proposed to be consistent with approximately a 12% reduction in stroke risk over 20 years. Dietary interventions of this magnitude have thus been proposed63 and would seem to be appropriate advice for the general population, in addition to prospective chiropractic patients.

Conclusion 

All signs from the foregoing discussion point to aberrations of arterial structure brought on by elevated levels of homocysteine. When applied to cervical manipulations, this body of evidence suggests that the inherent fragility of the arterial wall of the cerebrovascular system rather than any trauma associated with maneuvers by the attending physician is the major culprit regarding arterial dissections. The actual risk of CVAs that can be directly attributable to spinal manipulation may be reduced to far less conspicuous levels when compared with everyday lifestyle risks and those brought on by medications. Certainly, the propagation of risk estimates attributable to visits to the chiropractor's office without adequate justification from data does not perform a useful service to the public; indeed, it does just the opposite. Homocysteine measurement as a clinical tool would appear to afford the chiropractic physician a means to bring the actual risks of CVAs to even lower levels than those previously reported. In addition, nutritional counseling regarding the intake of increased folate might be expected to reduce elevated homocysteine levels and therefore reduce the risk of spontaneous VADs. At present, homocysteine determinations appear to be the most plausible means of assessing patients who are most at risk for CVAs from routine activities, let alone from cervical spinal manipulations.